Hereditary Inclusion Body Myopathy (HIBM, MIM 600737) is an autosomal recessive neuromuscular disorder characterized by adult onset, slowly progressive muscle weakness and atrophy. Serum creatine kinase levels are normal to slightly elevated and electromyograms show either a myopathic or a neuropathic pattern. Histologically, muscle fibers degenerate and develop cytoplasmic rimmed vacuoles and cytoplasmic or nuclear filamentous inclusions. No therapy currently exists for HIBM.
The myopathy results from mutations in GNE gene, coding for the bifunctional enzyme UDP-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK). A GNE founder mutation (M712T) was originally described in Persian-Jewish HIBM families, but numerous other mutations in GNE are now reported in patients worldwide. GNE/MNK is ubiquitously expressed and catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid (Neu5Ac, sialic acid). The enzyme is feedback-inhibited by the downstream product, CMP-Neu5Ac. Neu5Ac is the most abundant mammalian sialic acid and is typically found as the terminal sugar on glycoconjugates, where it plays a role in a variety of cellular signaling functions. HIBM-associated GNE mutations, result in reduced activity of both GlcNAc 2-epimerase and ManNAc kinase activities; these decrements are considered responsible for reduced production of sialic acid.
The pathologic mechanism of the eventual muscle fiber degeneration of HIBM remains unknown. However, evidence suggests that decreased availability of sialic acid in muscle causes hyposialylation of muscle glycoproteins, whether involving glycans in general, O-linked glycans, polysialic acid on neural cell adhesion molecule (PSA-NCAM), or specific O-mannosylated glycosyl residues on α-dystroglycan. The O-mannosylated residues on α-dystroglycan govern interactions of α-dystroglycan with extracellular matrix proteins, and their deficiency is responsible for several congenital muscular dystrophies, including Walker-Warburg syndrome and Muscle-Eye-Brain disease.
While the above pathways that are implicated in the disease are known, no treatment for the disease has been found to date. Therefore, there is a need in the art for animal models in which the disease can be studied, and treatment regimens that can ameliorate the effects of the disease.